Warmed humidified inspired oxygen accelerates postoperative rewarming.

STUDY OBJECTIVE: To investigate the efficacy of warmed, humidified inspired oxygen (O(2)) for the treatment of mildly hypothermic postoperative patients. DESIGN: Prospective, randomized, unblinded clinical trial. SETTING: Postanesthesia care unit in a tertiary care hospital. PATIENTS AND INTERVENTIONS: 30 ASA physical status I, II, and III patients following intraabdominal surgical procedures were randomly assigned to receive either routine O(2) therapy (control group, n = 15), or warmed (42 degrees C) humidified O(2) (treatment group, n = 15) for the initial 90 postoperative minutes. MEASUREMENTS: Core (tympanic) temperature, dry mouth score and shivering score. MAIN RESULTS: Tympanic temperature was similar in both groups on admission ( approximately 35.8 degrees C). Rewarming rate in the first postoperative hour was greater in the treatment group (0.7 +/- 0.1 degrees C. hr(-1)) compared to the control group (0.4 +/- 0.1 degrees C. hr(-1)) (p = 0.03). Patients receiving the warmed, humidified O(2) had a lower incidence of dry mouth compared to the control group (p = 0.03). The incidence of shivering was low and similar in both groups. CONCLUSIONS: Warming and humidifying inspired O(2) hastens recovery from hypothermia in postoperative patients.

Dynamic ventilatory responses in rats: normal development and effects of prenatal nicotine exposure.

Infants of smoking mothers are at increased risk of SIDS, one cause of which is thought to be due to impaired ventilatory responses. We tested the hypotheses that prenatal nicotine exposure impairs the development of dynamic carotid chemoreceptor-driven ventilatory responses, and reduces the ability to lower metabolic rate in hypoxia. Osmotic minipumps were implanted into 20 pregnant rats at day 3 of gestation to deliver nicotine (6 mg/kg per day free base) or saline for 4 weeks. Minute ventilation was recorded breath by breath in rat pups at 3, 8 and 18 days (n = 6, 8 and 6) postnatal in response to 5-sec challenges of 100% O2 (Dejours test) and 5% O2 + 5% CO2. Carotid sinus nerve (CSN) responses to hypoxia and CO2 were recorded from 22 control and 17 nicotine-exposed preparations at ages between 3-20 days. Oxygen consumption (V(O)2) was measured in groups of pups at 3 days (n = 7 each for nicotine and control) and 8 days (n = 5 each for nicotine and control) in room air and 10% O2. There was no detectable effect of nicotine exposure on the development of CSN responses. Ventilatory responses to 5% O2-5% CO2 increased with age but did not differ between nicotine and control groups. Ventilatory responses to 100% O2 were unaffected by nicotine exposure at 8 and 18 days. However, the 3-day nicotine group showed no significant response to 100% O2 whereas V(E) was significantly reduced in the control group by 100% O2. There was no significant effect of nicotine exposure on the ability to reduce oxygen consumption in hypoxia at 3 or 8 days, but at 3 days, baseline (room air) variability in oxygen consumption was greater in the nicotine group. We conclude that nicotine exposure appears to result in abnormal ventilatory responses to withdrawal of baseline peripheral chemoreceptor drive during a period of early postnatal life. We speculate that a transient abnormality could contribute to a period of instability and increased vulnerability to challenges.

Chronic hypoxia abolished the postnatal increase in carotid body type I cell sensitivity to hypoxia.

The O2 sensitivity of carotid chemoreceptor type I cells is low just after birth and increases with postnatal age. Chronic hypoxia during postnatal maturation blunts ventilatory and carotid chemoreceptor neural responses to hypoxia, but the mechanism remains unknown. We tested the hypothesis that chronic hypoxia from birth impairs the postnatal increase in type I cell O2 sensitivity by comparing intracellular Ca2+ concentration ([Ca2+]i) responses to graded hypoxia in type I cell clusters from rats born and reared in room air or 12% O2. [Ca2+]i levels at 0, 1, 5, and 21% O2, as well as with 40 mM K+, were measured at 3, 11, and 18 days of age with use of fura 2 in freshly isolated cells. The [Ca2+]i response to elevated CO2/low pH was measured at 11 days. Chronic hypoxia from birth abolished the normal developmental increase in the type I cell [Ca2+]i response to hypoxia. Effects of chronic hypoxia on development of [Ca2)]i responses to elevated K+ were small, and [Ca2+]i responses to CO2 remained unaffected. Impairment of type I cell maturation was partially reversible on return to normoxic conditions. These results indicate that chronic hypoxia severely impairs the postnatal development of carotid chemoreceptor O2 sensitivity at the cellular level and leaves responses to other stimuli largely intact.

Postnatal maturation of carotid body and type I cell chemoreception in the rat.

The site of postnatal maturation of carotid body chemoreception is unclear. To test the hypothesis that maturation occurs synchronously in type I cells and the whole carotid body, the development of changes in the intracellular Ca2+ concentration responses to hypoxia, CO2, and combined challenges was studied with fluorescence microscopy in type I cells and compared with the development of carotid sinus nerve (CSN) responses recorded in vitro from term fetal to 3-wk animals. Type I cell responses to all challenges increased between 1 and 8 days and then remained constant, with no multiplicative O2-CO2 interaction at any age. The CSN response to hypoxia also matured by 8 days, but CSN responses to CO2 did not change significantly with age. Multiplicative O2-CO2 interaction occurred in the CSN response at 2-3 wk but not in younger groups. We conclude that type I cell maturation underlies maturation of the CSN response to hypoxia. However, because development of responses to CO2 and combined hypoxia-CO2 challenges differed between type I cells and the CSN, responses to these stimuli must mature at other, unidentified sites within the developing carotid body.

Resetting and postnatal maturation of oxygen chemosensitivity in rat carotid chemoreceptor cells.

1. Carotid chemoreceptor sensitivity is minimal immediately after birth and increases with postnatal age. In the present study we have investigated the peri- and postnatal developmental time course of [Ca2+]i responses to hypoxia in clusters of type I cells isolated from near-term fetal rats and rats that were 1, 3, 7, 11, 14 and 21 days old, using the Ca2+-sensitive fluoroprobe fura-2. 2. In type I cells from all age groups a graded increase in [Ca2+]i occurred in response to lowering the PO2 from 150 mmHg to 70, 35, 14, 7, 2 and 0 mmHg. The graded [Ca2+]i response to hypoxia was hyperbolic at all ages. 3. Type I cells from rats near-term fetal to 1 day old exhibited small [Ca2+]i responses, mainly to the most severe levels of hypoxia. After day 1, an increase in the [Ca2+]i responses to submaximal hypoxia stimulation resulted in a rightward shift in the O2 response curve. Using the Delta[Ca2+]i between 35 and 2 mmHg PO2 as an index of O2 sensitivity, type I cell O2 sensitivity increased approximately 4- to 5-fold between near-term fetal to 1 day old and 11 to 14 days of age. 4. Exposure to elevated extracellular potassium (10, 20 and 40 mM K+) caused a dose-dependent [Ca2+]i rise in type I cells from all age groups. There were no age-related changes in [Ca2+]i responses to any level of K+ between near-term fetal and 21 days. 5. We conclude that the maximal type I cell [Ca2+]i response to anoxia, as well as the sensitivity to submaximal hypoxic stimulation, of rats aged from near-term fetal to 21 days depends on the level of postnatal maturity. The lack of an age-related increase in the [Ca2+]i response to elevated K+ during the timeframe of maximal development of O2 sensitivity suggests that resetting involves maturation of O2 sensing, rather than non-specific developmental changes in the [Ca2+]i rise resulting from depolarization.

Lack of induction of substance P gene expression by hypoxia and absence of neurokinin 1-receptor mRNAs in the rat carotid body.

Peripheral chemoreceptors are commonly thought to respond to hypoxia by releasing neurotransmitters from the type 1 cells of the carotid body; these molecules then bind to post-synaptic receptors on the carotid sinus nerve. The tachykinin substance P (SP) may act as an important neurotransmitter/neuromodulator in hypoxic chemotransmission in peripheral arterial chemoreceptors. In order to elucidate the role of SP in modulating hypoxic chemotransmission, we have used quantitative in situ hybridization histochemistry, to determine the effect of hypoxia on SP gene induction, and the localization of neurokinin 1 (NK-1) receptor mRNA in the carotid body and petrosal ganglia complex in rats at 21 days post-natal age. For comparison, we also determined: (1) the effect of hypoxia on tyrosine hydroxylase (TH) gene induction and (2) the localization of the mRNA encoding the D2-dopamine receptor. SP mRNA was not detected in the rat carotid body during normoxia and its expression was not induced after a 1 h of exposure to hypoxia (10% O2/90% N2), a stimulus that was sufficient to cause a significant increase (P < 0.01) in TH mRNA levels in the carotid body. Both SP and TH mRNAs were abundantly expressed in multiple cells in the petrosal and the jugular ganglia. However, these mRNAs were not co-localized and SP and TH mRNA levels were not affected by hypoxia in these ganglia. Although D2-dopamine receptor mRNA was abundantly expressed in the rat carotid body, we found no evidence of NK-1 receptor mRNA in the carotid body. In contrast, both NK-1 receptor mRNA and D2-dopamine receptor mRNA were present in petrosal ganglion cells. In the rat, SP does not appear to modulate hypoxic chemotransmission by being made in and released from type 1 cells in the carotid body, and neither does SP modulate the activity of type 1 cells by binding to NK-1 receptors on these cells.

The cardiorespiratory response to anoxia: normal development and the effect of nicotine.

Maternal smoking increases the risk of the sudden infant death syndrome (SIDS) 2-4-fold. The mechanism is unknown but may be related to hypoxia responses. Recovery from hypoxic apnea by young mammals depends on gasping and bradycardia. We asked whether prenatal nicotine exposure, reported to reduce hypoxic survival in 2 day old rat pups, acted by impairing gasping or bradycardia. Pregnant rats were infused throughout gestation and 1 week postnatally with nicotine tartrate (NIC) 12 mg/kg per day or saline (CON). Maternal plasma nicotine was 134.4 +/- 42 ng/ml, significantly reducing pup body weight. Pups at 3-28 days were exposed to anoxia (97% N2/3% CO2) until gasping ceased, while breathing and heart rate were recorded. NIC and CON groups were not significantly different at any age, in baseline heart rate, respiratory rate, the time course for bradycardia, time to gasp onset, duration of gasping, or number of gasps, although most of these variables declined significantly with age. We conclude that responses to anoxia are not affected by prenatal high-dose nicotine.

Effect of nicotine exposure on postnatal ventilatory responses to hypoxia and hypercapnia.

The risk of SIDS is increased up to fourfold by maternal smoking, by an unknown mechanism. We tested the hypothesis that prenatal nicotine exposure can cause abnormal postnatal development of breathing control. Osmotic minipumps were implanted into pregnant rats to deliver either nicotine bitartrate (6 mg kg-1 day-1) (NIC) or saline (CON) throughout gestation and for 1 week postnatal. NIC and CON rat pups from 4 age groups (means 3, 8, 18 and 34 days) were studied. Ventilation was recorded at 30 degrees C in air and after 10 min at FIO2 = 0.1 and 0.15, and at FICO2 = 0.05. Ventilatory responses to FIO2 = 0.1 and FICO2 = 0.05 showed significant changes with age but were unaffected by NIC at all ages. The weak respiratory responses to FIO2 = 0.15 were unaffected by NIC or age. Oxygen consumption in normoxia and hypoxia, and hypoxic depression of oxygen consumption, declined with age but were not affected by NIC. We conclude that NIC exposure alone has no detectable effect on the postnatal development of respiratory responses to moderate levels of hypoxia or hypercapnia for short periods. However, effects of NIC on the responses to more severe or prolonged stimuli cannot be ruled out.

Mechanisms of carotid chemoreceptor resetting after birth. In vitro studies.

The results of these studies are consistent with the hypothesis that carotid chemoreceptor type-I cell resetting occurs, at least in part, at the level of the type-I cell. Furthermore, we have developed an in vitro model of newborn type-I cell resetting, in which freshly isolated glomus cells from newborns exhibit small, immature [Ca2+]i response to anoxia, but-after 72 hours in culture-[Ca2+]i responses convert to adult magnitude and profile. Finally, work so far suggests that glomus cell resetting in this model is modulated by oxygen tension. The mechanisms of glomus cell resetting remain unknown. Resetting of O2 sensitivity could result from withdrawal of tonic inhibitory influences present in vivo, changes in the oxygen sensor itself, changes in ion channel expression, modulation, and function, or other mechanisms occurring around the time of birth. Additional work is needed to determine the mechanisms of glomus cell resetting at the cellular level, and the role of O2 tension and other potential modulators of resetting.

Developmental changes in intracellular Ca2+ response of carotid chemoreceptor cells to hypoxia.

The carotid chemoreceptor response to hypoxia is weak just after birth and increases during postnatal development. The mechanisms underlying chemoreceptor maturation are unknown. We tested the hypothesis that carotid chemoreceptor maturation occurs at the glomus cell level by measuring intracellular calcium ([Ca2+]i) mobilization in response to hypoxia, anoxia, and NaCN in freshly dissociated cells from newborn vs. adult rabbit carotid bodies. Cells were loaded with fura 2 and superfused at 37 degrees C with balanced salt solution equilibrated with 5% CO2. [Ca2+]i mobilization in response to 3-min challenges of hypoxia (PO2 approximately 15 mmHg), anoxia (PO2 approximately 0 mmHg), and NaCN (1 mM) was measured using a digital imaging microscope. The fluorescence intensity ratio was used to calculate [Ca2+]i. Peak [Ca2+]i responses to all three challenges were three- to fivefold greater in glomus cells from adult compared with newborn carotid chemoreceptors. In addition, the average normoxic [Ca2+]i baseline was approximately threefold higher in the adult glomus cells. These results suggest that carotid chemoreceptor glomus cell sensitivity to natural stimuli, as reflected by the [Ca2+]i response, depends on the level of postnatal maturity.

Effects of domperidone on neonatal and adult carotid chemoreceptors in the cat.

It has been postulated that the weak carotid chemoreceptor responses of neonatal mammals may be due to inhibition produced by high levels of endogenous dopamine release or exaggerated sensitivity to dopaminergic inhibition. This was studied by measuring the effect of domperidone, a selective dopamine D2-receptor antagonist, on the carotid chemoreceptor response to O2 and CO2 in anesthetized neonatal and adult cats. The animals were exposed to four levels of isocapnic O2 (arterial PO2 of approximately 35-45, 55-65, 80-90, > 300 Torr) and four levels of isoxic CO2 (end-tidal PCO2 of approximately 21, 40, 58, and 78 Torr) before and after D2-receptor blockade. Whole nerve activity was recorded from the carotid sinus nerve (CSN). Both neonatal and adult cats increase CSN activity during hypoxia and hypercapnia (P < 0.001). Domperidone caused an increase in CSN activity at all O2 levels in adults (P < 0.01) but only during hypoxia in neonates (P < 0.001). Domperidone caused an increase in CSN activity during normo- and hypercapnia in adults but only during hypercapnia in neonates (P < 0.001). Domperidone approximately doubled an index of hypoxic sensitivity in the normoxia-hypoxia range (100 to 40 Torr) in the neonatal group but had little effect on sensitivity to hypoxia in adults. We conclude that the inhibitory role of endogenous dopamine in the carotid chemoreceptors changes with postnatal development.

Postnatal maturation of carotid chemoreceptor responses to O2 and CO2 in the cat.

This study aimed to characterize neural responses of the carotid chemoreceptors of the maturing cat to natural stimuli and to determine the time course of carotid chemoreceptor development from the neonatal period to adulthood. Carotid sinus nerve (CNS) responses to O2 and CO2 were studied in cats at 1, 4, and 8 wk of age and in adult cats (n = 6 at each age). Pentobarbital sodium-anesthetized cats were exposed to three levels of O2 (arterial PO2 = 40-45, 80-90, and > 300 Torr) at five levels of arterial PCO2 (22, 35, 48, 63, and 75 Torr) while the moving average of whole nerve output from the CSN was recorded. Ganglioglomerular nerves were sectioned. All cats at every age increased CSN activity during hypoxia. However, the CSN response to hypoxia was not sustained in some immature cats. Of the cats that sustained CSN activity during hypoxia, four of the six 1-wk-old cats showed a biphasic pattern of response, with an initial overshoot followed by a steady level of discharge. Older cats did not exhibit this pattern. CNS sensitivity to hypoxia was weakest in 1-wk-old kittens but increased to nearly adult levels by 4 wk of age. Carotid chemoreceptor responses to CO2 were also smallest in 1-wk-old kittens and increased with maturation. However, unlike hypoxia responses, CO2 sensitivity during hypoxia continued to develop between 8 wk and adulthood. O2-CO2 interaction did not become significant until after 4 wk of age. Thus, carotid chemoreceptor responses to both O2 and CO2 are weak in newborn cats and increase during postnatal development.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of in utero phrenic nerve section on the development of collagen and elastin in lamb lungs.

Interference with fetal breathing movements is known to retard morphologic development of the lung and to reduce compliance. We hypothesized that the lower compliance might be in part due to effects on lung structural proteins. We studied the effects of phrenic nerve section in utero on lung compliance and on the lung contents of collagen, elastin, and DNA. At 110 to 112 days of gestation, one fetal lamb in each of 12 twin pregnancies had either both phrenic nerves cut (PX) or a sham operation (S). The other twin was left unoperated (Upx, Us) as a control. They were killed 14 to 22 days later, and the concentrations in lung parenchyma of collagen (as hydroxyproline HPro), elastin, and DNA were measured, together with lung compliance and dry and wet weight. Paired comparisons were made (PX versus Upx and S versus Us). Both operated groups (PX, S) had smaller lungs with lower water content than did their unoperated twins. Absolute static compliance in PX was reduced, but compliance relative to lung weight was unchanged, and there was no significant difference between S and Us. There were no significant effects of PX on the concentrations of HPro, elastin, and DNA, or on the elastin/collagen ratio. Compliance was not correlated with either HPro or elastin content. HPro content increased significantly with gestational age in all groups. It is concluded that phrenic nerve section retards the increase of lung compliance and possibly air space, but it does not affect the overall rate of lung cell proliferation or of deposition of elastin or collagen.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hyperoxia (PaO2 50-90 mmHg) on fetal breathing movements in the unanaesthetized fetal sheep.

Hypoxia inhibits fetal breathing movements but after birth it stimulates breathing. These differences have long been thought to involve central nervous inhibitory mechanisms. Such mechanisms might exert a tonic inhibition of fetal breathing movements at normal fetal PaO2 and the rise in PaO2 at birth might lift this inhibitory effect. To test this hypothesis 7 fetal sheep were chronically instrumented at 125-130 days for recording electrocortical activity (ECoG), and the electromyograph (EMG) activity of the diaphragm and neck muscles. Catheters were placed in a fetal carotid and a brachial artery and in the fetal trachea. For an extracorporeal membrane oxygenation system a 12 F gauge silastic catheter was placed in the right atrium for draining fetal blood and a 9.6 F gauge catheter was placed in a carotid artery to return oxygenated blood. Three days after operation the fetuses were connected to the extracorporeal membrane oxygenation system and fetal PaO2 was raised to 65.2 +/- 4.4 mmHg (SEM) for 6 to 19 h without changing pH or PaCO2. Neither the incidence of high voltage ECoG (48.5 +/- SEM 2.0% vs 52.8 +/- 3.3%) nor of fetal breathing movements (37.3 +/- 2.6% vs 23.8 +/- 5.9%) changed during the periods of hyperoxia. Since fetal breathing movements did not become continuous, we conclude that the lower PaO2 in the fetus compared to the neonate does not exert a tonic inhibitory influence on fetal breathing movements.

Effects of clonidine on breathing movements and electrocortical activity in the fetal lamb.

Clonidine is a recommended antihypertensive for use during pregnancy, although little is known of its fetal effects. This study examines the effects of clonidine on breathing and sleep-state cycling in fetal lambs. Clonidine was infused into a fetal lateral ventricle for up to 24 hours at 128 to 135 days' gestation. Control infusions of artificial cerebrospinal fluid had no effect. Clonidine infusion significantly reduced the incidence and episode duration of fetal breathing for the duration of the infusion period. Cycling of electrocortical activity became irregular and rapid, and the incidence of high-voltage electrocortical activity (equivalent to quiet sleep) was reduced. Fetal heart rate decreased but arterial pressure was unaffected. After infusion the breathing incidence and episode duration both increased significantly compared with control, with continuous high-amplitude breathing for several hours, whereas the incidence of high-voltage electrocortical activity remained low. Because lung development is promoted by fetal breathing, long-term use of clonidine during pregnancy could slow lung development by reducing fetal breathing activity.

Hypoxia and electrocortical activity in the fetal lamb: effects of brainstem transection and chemoreceptor denervation.

In order to investigate possible mechanisms for the effect of hypoxia on fetal electrocortical (ECoG) activity, the effects of 30 min of isocapnic hypoxia on ECoG were studied in three groups of unanaesthetized late-gestation fetal lambs in utero. One group was intact, in the second the brainstem was transected between the colliculi, and in the third the carotid sinus nerves and cervical vagosympathetic trunks were cut bilaterally to denervate the systemic arterial chemoreceptors. The incidence of high voltage (HV) ECoG activity was lower in brainstem-transected fetuses than in the other groups. All three groups showed an increased number of changes from low to high voltage and an increase in the incidence of HV activity at the onset of hypoxia, but the increases reached statistical significance only in the brainstem-transected group. It is concluded that the onset of hypoxia is often associated with an increase in HV ECoG activity, with the most consistent changes occurring after brainstem transection and similar but smaller increases in intact and denervated fetuses. Thus the response of fetal electrocortical activity to the onset of hypoxia does not depend on intact connections with the lower brainstem. However, the effect of hypoxia on fetal ECoG is minor and inconsistent and may be physiologically unimportant.

The effects of brain-stem section on the breathing and behavioural response to morphine in the fetal sheep.

In the unanesthetized fetal sheep the administration of morphine causes initial apnoea followed by hyperpnoea. We thought that a section of the brain at midcollicular level might separate these two effects. Therefore we sectioned the brain stem of five fetuses at 132 +/- 1 (SEM) days of gestation and compared their responses to morphine (17 experiments) with that observed in seven intact fetuses at similar gestational ages (15 experiments). Brain stem sections were confirmed morphologically and histologically. Morphine, 1 mg/kg was injected in the fetal jugular vein during low-voltage electrocortical activity (ECoG). We measured ECoG, eye movements, diaphragmatic activity, blood pressure and amniotic pressure. Sectioned fetuses before the administration of morphine had a complete dissociation between ECoG and breathing activity. With the administration of morphine we found: (i) the length of the apnoea was 139.8 +/- 15.5 min in sectioned fetuses and 17.0 +/- 5.8 min in intact fetuses (P less than 0.01); and (ii) there was no hyperpneic response in the sectioned fetus whereas the length of hyperpnoea in the intact group was 99.1 +/- 11.8 min (P less than 0.001). The results support the idea of two central distinct areas of action of morphine in the fetal brain. The absence of hyperpnoea in the sectioned fetuses suggests that neurons inhibiting the 'respiratory neurons' are located rostrally to the mid-collicular line.

Effects of the alpha 2-adrenergic agonist clonidine and its antagonist idazoxan on the fetal lamb.

1. The alpha 2-adrenergic agonist clonidine was given by aortic injection to three groups of unanaesthetized fetal lambs in utero near term. One group was intact, the second had the brain stem transected just above the pons, and the third had bilateral section of the carotid sinus nerves and cervical vagi. 2. Clonidine had similar effects in all three groups. Electrocortical activity entered a high-voltage, low-frequency episode: breathing, neck and limb movements ceased; arterial pressure remained unchanged or increased; heart rate fell or remained unchanged, and the variation in both heart rate and blood pressure was much reduced. This state lasted 10-20 min, and was followed by a period of up to 4 h during which the cycling of electrocortical activity was rapid and irregular. 3. The alpha 2-adrenergic antagonist idazoxan (0.5-2.0 mg I.A.) blocked all the actions of clonidine. When given alone it usually induced a short period of low-voltage electrocortical activity and stimulated breathing movements. These effects were present in both the intact and brain-stem-transected groups, though the stimulation of breathing was significantly reduced by brain-stem transection. There were no consistent effects on heart rate or blood pressure. 4. The effects of clonidine on fetal heart rate and electrocortical activity were similar to those described in adults, but it also had inhibitory effects, not present in adults, on fetal breathing and somatic movements.